Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9QW7Q0)

• DOT Name: ER lumen protein-retaining receptor 2 (KDELR2)
• Synonyms: ERD2-like protein 1; ELP-1; KDEL endoplasmic reticulum protein retention receptor 2; KDEL receptor 2
• Gene Name: KDELR2
• Related Disease:
  Advanced cancer
  Glioblastoma multiforme
  Measles
  Osteogenesis imperfecta, type 21
  Riley-Day syndrome
  Coronary heart disease
  Osteogenesis imperfecta
• UniProt ID: ERD22_HUMAN
• Pfam ID: PF00810
• Sequence:
  MNIFRLTGDLSHLAAIVILLLKIWKTRSCAGISGKSQLLFALVFTTRYLDLFTSFISLYN
  TSMKVIYLACSYATVYLIYLKFKATYDGNHDTFRVEFLVVPVGGLSFLVNHDFSPLEILW
  TFSIYLESVAILPQLFMISKTGEAETITTHYLFFLGLYRALYLVNWIWRFYFEGFFDLIA
  VVAGVVQTILYCDFFYLYITKVLKGKKLSLPA
• Function: Membrane receptor that binds the K-D-E-L sequence motif in the C-terminal part of endoplasmic reticulum resident proteins and maintains their localization in that compartment by participating to their vesicle-mediated recycling back from the Golgi. Binding is pH dependent, and is optimal at pH 5-5.4.
• KEGG Pathway: Vibrio cholerae infection (hsa05110)
• Reactome Pathway:
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  COPI-mediated anterograde transport (R-HSA-6807878)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Measles	DISXSUID	Strong	Biomarker	[2]
Osteogenesis imperfecta, type 21	DISJ2UMP	Strong	Autosomal recessive	[3]
Riley-Day syndrome	DISJZHNP	Strong	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[5]
Osteogenesis imperfecta	DIS7XQSD	Supportive	Autosomal dominant	[3]

16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[11]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[12]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[15]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ER lumen protein-retaining receptor 2 (KDELR2).	[21]

References

• [1] KDELR2 Promotes Glioblastoma Tumorigenesis Targeted by HIF1a via mTOR Signaling Pathway.Cell Mol Neurobiol. 2019 Nov;39(8):1207-1215. doi: 10.1007/s10571-019-00715-2. Epub 2019 Jul 25.
• [2] KDELR2 Competes with Measles Virus Envelope Proteins for Cellular Chaperones Reducing Their Chaperone-Mediated Cell Surface Transport.Viruses. 2019 Jan 4;11(1):27. doi: 10.3390/v11010027.
• [3] Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2. Am J Hum Genet. 2020 Nov 5;107(5):989-999. doi: 10.1016/j.ajhg.2020.09.009. Epub 2020 Oct 13.
• [4] Kinetin in familial dysautonomia carriers: implications for a new therapeutic strategy targeting mRNA splicing. Pediatr Res. 2009 Mar;65(3):341-6.
• [5] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [6] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [13] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [14] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [15] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [16] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [17] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.